Advances in the design and development of chemical modulators of the voltage-gated potassium channels KV7.4 and KV7.5.

Abstract

Introduction: Hypertension remains a major public health concern, with significant morbidity and mortality worldwide. Despite the availability of various antihypertensive medications, blood pressure control remains suboptimal in many individuals. During the last decades, K_V7.4 and K_V7.5, which were already known from the view of neuronal regulation, emerged as possible important players in the regulation of vascular tone and blood pressure.

Areas covered: This review covers physiological functions and current advancements in the development of K_V7.4 and K_V7.5 channel modulators. The authors highlight the structural elements likely to be important for the future design of K_V7 subtype-selective modulators, underscoring their potential as an innovative hypertension treatment.

Expert opinion: Extensive research has been focused on targeting neuronal K_V7.2 and K_V7.3 channels, while K_V7.4 and K_V7.5 attracted less attention. Many of the developed compounds represent derivatives of flupirtine or retigabine, whereby subtype channel selectivity has only been demonstrated for a handful of individual compounds. Novel substances address additional sites within the binding pocket by incorporating new functional groups. A comprehensive and systematic evaluation of a compound set with significant subtype selectivity should be performed. The discovery of new highly active, less toxic, and selective compounds, therefore, remains the goal of further research in the coming years.